Synthesis of 5-(Fluoroalkyl)isoxazole Building Blocks by Regioselective Reactions of Functionalized Halogenoximes

Abstract

A comprehensive study on the synthesis of 5-fluoroalkyl-substituted isoxazoles starting from functionalized halogenoximes is reported. One-pot metal-free [3 + 2] cycloaddition of CF3-substituted alkenes and halogenoximes bearing ester, bromo, chloromethyl, and protected amino groups was developed for the preparation of 5-trifluoromethylisoxazoles. The target 3,5-disubstituted derivatives were obtained in a regioselective manner in good to excellent yield on up to 130 g scale. 5-Fluoromethyl- and 5-difluoromethylisoxazoles were synthesized by late-stage deoxofluorination of the corresponding 5-hydroxymethyl or 5-formyl derivatives, respectively, in turn prepared via metal-free cycloaddition of halogenoximes and propargylic alcohol. An alternative approach based on nucleophilic substitution in 5-bromomethyl derivatives was found to be more convenient for the preparation of 5-fluoromethylisoxazoles. Reaction of isoxazole-5-carbaldehydes with the Ruppert–Prakash reagent was used for the preparation of (β,β,β-trifluoro-α-hydroxyethyl)­isoxazoles. Utility of described approaches was shown by multigram preparation of side-chain functionalized mono-, di-, and trifluoromethylisoxazoles, for example, fluorinated analogues of ABT-418 and ESI-09.

Synthesis of trifluoromethyl or trifluoroacetyl substituted heterocyclic compounds from trifluoromethyl‐α,β‐ynones

“…Based on the importance of trifluoromethylpyrazole ring, the effective construction of trifluoromethylpyrazole ring has gained much attention, [38][39][40] including dehydrative condensation of hydrazines with aldehydes or ketones, and then reacting with organofluorine reagents, such as Togni's reagents, [41] 2-bromo-3,3,3-trifluoropropene, [42] and so on. In addition, the synthesis method of trifluoromethylated isoxazoles has also been developed in a certain amount, [43,44] although the synthesis of trifluoromethylpyrazolo[1,5-a]pyridines is rare.…”

An isoxazole strategy for the synthesis of 4-oxo-1,4-dihydropyridine-3-carboxylates

“…Isoxazoles 11a – f were prepared by cycloaddition of nitrile oxides, generated from N -hydroxyimidoyl chlorides 7a – f , to propargyl halides [ 29 ], followed by the cyanation of the resulted isoxazoles 8a – f to cyanides 9a – f using Me 2 C(OH)CN/(Me 2 N) 2 C=NH [ 29 ], their acid hydrolysis, followed by esterification of the resulting acids 9a – f with diazomethane. 4-Iodoisoxazoles 12a – f , necessary for the preparation of 3,4-disubstituted isoxazoles, were obtained by iodination of 11a , c , e – g with NIS/TFA [ 30 ]. The reaction of 11d gave the product of double iodination 12c .…”

2‐Bromo‐3,3,3‐Trifluoropropene: A Versatile Reagent for the Synthesis of Fluorinated Compounds

“…Recently, Grygorenko and co‐workers reported the one‐pot [3+2] cycloaddition of halogenoximes 77 with BTP under metal‐free conditions (Scheme 36). [43] This reaction provided an efficient method for the synthesis of various 5‐trifluoromethylisoxazoles 78 with high regioselectivity. A series of functional groups can be tolerated, such as ester and protected amino groups.…”

“…[24][25][26][27][28][29][30][31][32] Interestingly, the application of BTP as a coupling partner to the CÀ H bond functionalization would be of significant value for the synthesis of trifluoromethylated compounds. [33,34] Furthermore, due to its unique structure, BTP has recently been utilized as a C 2 synthon in cycloaddition reactions for the construction of trifluoromethyl-containing (hetero)cyclic compounds, such as cyclopropane, [35] cyclobutene, [36] pyrazoles, [37][38][39][40][41] isoxazole, [42,43] benzoxazoles, [44] benzofuran and indole derivatives. [45] Other reactions have also been reported sporadically, such as S N 2'-type reactions [46,47] and intermolecular Stetter reactions.…”